Efficacy and Safety of Oral GLP-1 RA Orforglipron on Weight and Glycemic Control According to Diabetes Status: A Systematic Review and Meta-Analysis.

Excess body weight and poor metabolic control remain major contributors to cardiometabolic disease, highlighting the need for effective therapeutic options. This meta-analysis aimed to evaluate the efficacy and safety of once-daily oral orforglipron in obese adults with and without diabetes. Searches were conducted across four databases through November 2025. Five randomized controlled trials (n = 6140) were included. Orforglipron produced consistent, dose-dependent reductions in body weight, ranging from modest losses at 3 mg to more than 6 kg at 36 mg in patients with diabetes. Individuals without diabetes experienced greater weight reductions, approaching 12 kg at the highest dose. Significant improvements in body mass index, waist circumference, and glycated hemoglobin (HbA1c; -1.29%) were also observed. Gastrointestinal adverse events increased with higher dose, and no significant difference in the incidence of acute pancreatitis was identified. Overall, orforglipron demonstrated clinically meaningful metabolic benefits with an acceptable safety profile.